Publications

AIMS

Genetic and pharmacological studies have shown that impairment of the nitric oxide (NO) synthase (NOS) pathway is associated with hypertension and insulin-resistance (IR). In addition, inhibition of NOS by the endogenous inhibitor, asymmetric dimethylarginine (ADMA), may also result in hypertension and IR. On the other hand, overexpression of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that metabolizes ADMA, in mice is associated with lower ADMA, increased NO and enhanced insulin sensitivity. Since DDAH carries a farnesoid X receptor (FXR)-responsive element, we aimed to upregulate its expression by an FXR-agonist, INT-747, and evaluate its effect on blood pressure and insulin sensitivity.

METHODS AND RESULTS

In this study, we evaluated the in vivo effect of INT-747 on tissue DDAH expression and insulin sensitivity in the Dahl rat model of salt-sensitive hypertension and IR (Dahl-SS). Our data indicates that high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls.

CONCLUSION

Our study may provide the basis for a new therapeutic approach for IR by modulating DDAH expression and/or activity using small molecules.

Hispanic women in the USA have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case-control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1 and rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 [95% confidence interval (CI) = 0.50-1.15] for low IA ancestry and 1.38 (95% CI = 1.04-1.82) for high IA ancestry (P interaction 0.02). The ORs for association at RELN were 0.87 (95% CI = 0.59-1.29) and 1.69 (95% CI = 1.04-2.73), respectively (P interaction 0.03). At the TLR1 locus, the ORs for women homozygous for the rare allele were 0.74 (95% CI = 0.42-1.31) and 1.73 (95% CI = 1.19-2.52) (P interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of 3 of the 10 previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.

BACKGROUND

Cleft lip, with or without cleft palate (CL±P), is the most common craniofacial anomaly in newborns. The incidence of CL±P varies among different ethnic populations and is presumed to be higher in developing countries. In the Middle East, the incidence has variably been reported as 0.3 to 2.19 per 1000 live births and is generally regarded as similar to Caucasians. There is currently no literature reporting the incidence of clefting in Palestinians living in the territories. Reports from Palestinian populations in Israel and Jordan infer an incidence of 1.39 per 1000 live births. However, the reported incidence in stable populations may not reflect the actual incidence of clefting in the territories.

METHODS

This is a retrospective study examining all newborn records at Makassed Maternity Hospital in Jerusalem between January 1, 1986, and December 12, 1995. Data were collected by the senior author (A.D.) and interpreted by coauthors. Frequencies were established based on the number of isolated and nonisolated CL±P born during this time period.

RESULTS

During the 10-year period from January 1, 1986, to December 12, 1995, there were 33,239 live births. Among these births, there were 35 isolated and nonisolated combined CL±P born (1.05/1000 live births).

CONCLUSIONS

Based on this limited data set from a single, tertiary referral hospital, we conclude that the prevalence rate of CL±P among a Palestinian population may be less than that reported in surrounding areas. However, more broadly based studies using nationalized birth registries are required to determine an accurate prevalence rate of CL±P among Palestinians.